Abstract
Chronic pain is a significant symptom in patients with autoimmune encephalomyelitis, such as multiple sclerosis and neuromyelitis optica. The most commonly used animal model of these diseases is experimental autoimmune encephalomyelitis (EAE). We previously reported that evoked pain, such as mechanical allodynia, was improved by an anti-IL-6 receptor antibody in EAE mice. However, few reports have evaluated spontaneous pain in EAE mice. Here, we assessed spontaneous pain in EAE mice by utilizing the Mouse Grimace Scale (MGS, a standardized murine facial expression-based coding system) and evaluated the influence of an anti-IL-6 receptor antibody (MR16-1). EAE was induced in female C57BL/6J mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein 35–55 emulsified in adjuvant and administration of pertussis toxin. Mice were placed individually in cubicles and filmed for about 10 min. Ten clear head shots per mouse from the video recording were given a score of 0, 1, or 2 for each of three facial action units: orbital tightening, nose bulge, and ear position. Clinical symptoms of EAE were also scored. Measurement of 5-HT in the spinal cord and functional imaging of the periaqueductal gray (PAG) were also performed. Compared with control mice, MGS score was significantly higher in EAE mice. MR16-1 prevented this increase, especially in pre-onset EAE mice. Promotion of spinal 5-HT turnover and reduction of PAG activity were observed in pre-onset EAE mice. These results suggest that MR16-1 prevented spontaneous pain developed before EAE onset.
Highlights
Chronic pain is a major symptom associated with demyelinating autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS) and neuromyelitis optica (NMO)
Checking the relationship between periaqueductal gray (PAG) function and mouse grimace scale (MGS) score revealed a negative correlation between blood oxygenation level-dependent (BOLD) signal intensity in the PAG and MGS score (Figure 2F). This is the first report to indicate that anti-IL-6 receptor antibodies prevented spontaneous pain as evaluated by MGS score in EAE mice
A previous report mentioned that it cannot be excluded that the MGS scores in post-onset EAE mice may be influenced by demyelination of lower motor neurons resulting in a compromised ability to exhibit facial expressions [27]
Summary
Chronic pain is a major symptom associated with demyelinating autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS) and neuromyelitis optica (NMO). It has been reported that ∼50–80% of patients with MS or NMO feel severe pain [1,2,3], and neuropathic pain is the most prevalent and most difficult to treat in these patients [4, 5]. Proinflammatory cytokines such as interleukin-6 (IL-6) can be important factors in neuropathic pain [6]. We previously reported that a rat anti-mouse IL6 receptor monoclonal antibody (MR16-1) improved mechanical allodynia in experimental autoimmune encephalomyelitis (EAE) mice [12], which is a well-established animal model of CNS autoimmune disease, and causes widespread CNS inflammation, demyelination, and locomotor impairments [13]. Some studies have demonstrated that EAE mice show neuropathic pain behavior [14,15,16]
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